Progress 03/15/19 to 03/14/24
Outputs
Target Audience:Throughout the entire project period, we have successfully reached several target audiences through our USDA-supported project. These audiences include: (1) nutrition and food scientists, (2) undergraduate students in nutrition/dietetics, and (3) laypersons interested in diet and health. Nutrition and food scientists were engaged via the publication of full-length research papers in scientific journals, presentations at international scientific meetings (e.g., American Society for Nutrition; Federation of American Societies for Experimental Biology). Project Director Bruno also provided numerous invited scientific presentations at campus centers, departments, and other nutrition departments across the United States. Undergraduate students were educated both in the classroom and through field experiences in nutrition research, focusing on the health benefits of phytochemicals and methodologies to assess their efficacy and safety. Furthermore, The Ohio State University and other media services globally disseminated knowledge through a press release sharing preliminary findings of our USDA/NIFA-supported research, which demonstrated that green tea polyphenols improve gut health and glucose homeostasis in both healthy individuals and those with metabolic syndrome. Across all audiences, the information provided emphasized scientific rigor, phytochemical safety and efficacy, the critical link between gut health and overall well-being, and translation of scientific evidence into consumer-friendly recommendations. Changes/Problems: The major challenge encountered in this project was the disruption caused by the global pandemic. The randomized controlled trial experienced a temporary halt in recruitment, and all project activities were paused for approximately six months due to the uncontrolled spread of coronavirus. However, once research activities resumed, we successfully completed the human trial, conducted all planned analyses, and achieved all study objectives. This was accomplished on a revised timeline, facilitated by a no-cost extension provided by USDA/NIFA. What opportunities for training and professional development has the project provided? During the project, undergraduate research assistants, including those engaged as interns and in a formal capacity, were provided with opportunities for experiential learning at the intersection of clinical nutrition, laboratory management, data collection, archival, and analysis. The project also offered advanced training in metabolomics and microbiome techniques for graduate students and postdoctoral researchers involved in the project. These individuals developed contemporary skills in sample preparation, analysis by LC-MS or 16S genomic sequencing, and bioinformatics. All graduate students and postdoctoral trainees received hands-on mentoring from the Project Director, which included preparing and disseminating their work in peer-reviewed scientific literature and presenting their findings at national scientific conferences and local presentations for laypersons. How have the results been disseminated to communities of interest? Project outcomes have been disseminated to relevant communities. In alignment with the research focus of the project, findings have been shared with the scientific community through publications and presentations. These included full-length research manuscripts, narrative reviews in peer-reviewed scientific journals, and book chapters in edited volumes. The topics covered management of endotoxin to alleviate cardiometabolic disorders, preclinical and clinical evidence detailing the anti-inflammatory health benefits and bioavailability of green tea catechins, and the role of microbiota and microbial-generated metabolites in mediating these benefits. The Project Director actively presented these findings at national scientific conferences, university centers, and departments of nutrition and food science. Additionally, several presentations were made to lay audiences in the community to facilitate research translation. We also collaborated with university media services to issue press releases related to our peer-reviewed publications, ensuring broader outreach to stakeholders who can benefit from the knowledge generated by this project. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Significant accomplishments have advanced our USDA-supported research project towards achieving its primary objective: investigating the gut-level anti-inflammatory activities of green tea to alleviate metabolic endotoxemia. We successfully completed a rigorous, randomized, placebo-controlled trial involving both healthy individuals and those with metabolic syndrome, yielding pivotal results. Our research, published by Zeng et al. (2024, Nutr Res), provides novel evidence that daily supplementation of green tea catechins significantly reduces circulating endotoxin levels (the primary outcome). This reduction is associated with decreased small intestinal permeability and intestinal inflammation, indicating green tea's potential to protect against and mitigate disease-inducing responses linked to poor cardiometabolic health. These benefits occurred without adverse effects and were independent of changes in body mass. This work sets the stage for continued research utilizing cryopreserved biospecimens to examine microbial metabolites, including short-chain fatty acids, bile acids, and catechin-derived valerolactones, as well as microbiota composition and functions that mediate the health benefits of green tea polyphenols. We also conducted a pharmacokinetics study in humans to examine the impact of obesity on the bioavailability of green tea catechins and their metabolism to valerolactones. Our findings, published by Sasaki et al. (2023, Antioxidants), revealed that the bioavailability of all green tea catechins is significantly reduced in obese individuals compared to healthy individuals. This reduction is attributed to decreased intestinal absorption without significant alteration in plasma elimination. Despite reduced catechin absorption, obesity status did not affect the generation and absorption of catechin-derived valerolactones, which showed higher absorption than catechins regardless of obesity status. These results support the hypothesis that microbial metabolites of catechins, which are more readily absorbed, may contribute to the anti-inflammatory activities of green tea catechins. Extending this work, we developed a novel multi-organ system mathematical model to describe the whole-body trafficking of green tea catechins. Our report, published by Hodges et al. (2023, Nutrients), provides evidence that subtle differences in the chemical structure of green tea catechins affect their systemic accumulation. Specifically, the interaction of gallation and B-ring dihydroxylation significantly extended plasma residence time and influenced transfer dynamics across various body compartments. This multi-compartment model, pending validation in future studies, suggests that these structural interactions affect catechin catabolism in a tissue-specific manner, enhancing their potential bioactivity. Collectively, the outcomes of this project have yielded impactful knowledge that advances the understanding of the health benefits of green tea polyphenols. Building on observational evidence that greater consumption of green tea protects against cardiovascular disease, our controlled studies demonstrate that green tea intake equivalent to approximately five daily servings effectively manages inflammation-inducing responses driving obesity-associated metabolic dysfunction. Furthermore, our findings provide a foundation for future clinical practices that advocate a "food-first" approach, considering that each catechin, due to its unique bioavailability and trafficking profile, differentially supports health outcomes. Continued investigation of the interaction between green tea catechins and the gut microbiota will inform precision nutrition-based dietary recommendations to best alleviate cardiometabolic risk in humans.
Publications
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2023
Citation:
RS Bruno. (2023). From Man to Mouse and Back To Man: Cardiometabolic Benefits of Green Tea Catechins Along The Gut-Liver Axis. Federation of the Society for Experimental Biology and Medicine Summer Conference: Nutritional Immunology Across the Lifespan; Melbourne, FL.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2023
Citation:
RS Bruno. (2023). Gut-Level Anti-inflammatory Activities Of Green Tea Catechins In MetS Persons: A Randomized Controlled Trial. USDA Multi-State Conference, University of Hawaii; Honolulu, HI.
- Type:
Other
Status:
Other
Year Published:
2023
Citation:
RS Bruno. (2023). From Man to Mouse and Back To Man: Cardiometabolic Benefits of Green Tea Catechins Along The Gut-Liver Axis. Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences; Little Rock, Arkansas.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2024
Citation:
M Zeng, JK Hodges, S Cao, GY Sasaki, A Pokala, Y Vodovotz, G Brock, Z Yu, J Zhu, RS Bruno. (2024). Improved gut health by green tea extract confection in metabolic syndrome and healthy adults occurred without affecting short-chain fatty acids and microbiota diversity. Nutrition: International Meeting for the American Society for Nutrition (Chicago, IL). Poster Presentation.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2023
Citation:
M Zeng, JK Hodges, GY Sasaki, S Cao, A Pokala, Y Vodovotz, G Brock, Z Yu, J Zhu, RS Bruno. (2023). Green tea extract confection alleviates endotoxemia without affecting systemic inflammation in healthy adults and those with metabolic syndrome. Nutrition: International Meeting for the American Society for Nutrition (Boston, MA). Abstract/Poster.
- Type:
Book Chapters
Status:
Published
Year Published:
2023
Citation:
P Dey and RS Bruno. (2023). Green Tea Catechins and Nonalcoholic Fatty Liver Disease. In: Dietary Supplements With Antioxidant Activity: Understanding Mechanisms and Potential Health Benefits (edited by Alasalvar, Shahidi, and Ho). Food Chemistry, Function and Analysis No. 39. Royal Society of Chemistry. doi: 10.1039/9781839166112
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2024
Citation:
RS Bruno. (2024). Is Green Tea Good For My Heart Health? Global Tea Institute for the Study of Tea Culture and Science at University of California-Davis. 9th Annual Colloquium: Tea In A Changing World.
- Type:
Other
Status:
Other
Year Published:
2023
Citation:
RS Bruno. (2023). Anti-inflammatory Activities Of Green Tea Catechins Along The Gut-Liver Axis: Advances In Research Translation For Cardiometabolic Health. NIH Office of Dietary Supplements; Washington, DC.
- Type:
Other
Status:
Other
Year Published:
2022
Citation:
RS Bruno. (2022). From Man to Mouse and Back To Man: Cardiometabolic Benefits of Green Tea Catechins Along The Gut-Liver Axis. Department of Nutrition and Exercise Science, University of Missouri; Columbia, Missouri.
- Type:
Other
Status:
Other
Year Published:
2022
Citation:
RS Bruno. (2022). From Man to Mouse and Back To Man: Cardiometabolic Benefits of Green Tea Catechins Along The Gut-Liver Axis. Center for Advanced Functional Foods and Entrepreneurship (CAFFRE), The Ohio State University; Columbus, Ohio.
- Type:
Journal Articles
Status:
Published
Year Published:
2024
Citation:
Zeng M, Hodges JK, Pokala A, Khalafi M, Sasaki GY, Pierson J, Cao S, Brock G, Yu Z, Zhu J, Vodovotz Y, Bruno RS. A green tea extract confection decreases circulating endotoxin and fasting glucose by improving gut barrier function but without affecting systemic inflammation: A double-blind, placebo-controlled randomized trial in healthy adults and adults with metabolic syndrome. Nutrition Research. 2024;124:94-110. doi: https://doi.org/10.1016/j.nutres.2024.02.001.
- Type:
Journal Articles
Status:
Published
Year Published:
2023
Citation:
Hodges JK, Sasaki GY, Vodovotz Y, Bruno RS. Gallation and B-Ring Dihydroxylation Increase Green Tea Catechin Residence Time in Plasma by Differentially Affecting Tissue-Specific Trafficking: Compartmental Model of Catechin Kinetics in Healthy Adults. Nutrients. 2023;15(18):4021. doi: 10.3390/nu15184021.
- Type:
Journal Articles
Status:
Published
Year Published:
2023
Citation:
Pokala A, Quarles WR, Ortega-Anaya J, Jimenez-Flores R, Cao S, Zeng M, Hodges JK, Bruno RS. Milk-Fat-Globule-Membrane-Enriched Dairy Milk Compared with a Soy-Lecithin-Enriched Beverage Did Not Adversely Affect Endotoxemia or Biomarkers of Gut Barrier Function and Cardiometabolic Risk in Adults with Metabolic Syndrome: A Randomized Controlled Crossover Trial. Nutrients. 2023;15(14):3259.
- Type:
Journal Articles
Status:
Published
Year Published:
2024
Citation:
Pokala A, Kraft J, Taormina VM, Michalski M-C, Vors C, Torres-Gonzalez M, Bruno RS. Whole milk dairy foods and cardiometabolic health: dairy fat and beyond. Nutrition Research. 2024;126:99-122. doi: https://doi.org/10.1016/j.nutres.2024.03.010.
|
Progress 03/15/22 to 03/14/23
Outputs
Target Audience:During the past reporting period, we have reached several target audiences: (1) nutrition and food scientists, (2) undergraduate students in nutrition/dietetics, and (3) laypersons interested in diet and health. Nutrition and food scientists were reached via publication of full-length research papers in the scientific literature and abstracts presented at the American Society for Nutrition meeting. Dr. Bruno was also active in providing invited scientific presentations locally to campus centers and departments as well as to other nutrition departments in the United States. Undergraduate students were also educated in the classroom and/or through field experiences in nutrition research concerning the health benefits of phytochemicals and methodologies to assess their efficacy and safety. Lastly, The Ohio State University and other media services globally disseminated knowledge via a press release to share preliminary findings of our USDA/NIFA-supported research demonstrating that green tea polyphenols improve gut health to alleviate glucose homeostasis in both healthy persons and those afflicted by metabolic syndrome. Regardless of the population reached, all persons received information scientific rigor, phytochemical safety and efficacy, and knowledge concerning the intimate connection between gut health and host health towards achieving well-being. Changes/Problems:While no project objectives were modified, we did experience significant setbacks due to the global pandemic. Accordingly, institutional officials from USDA/NIFA were kind enough to grant a no-cost extension to accomplish all proposed work. With the submission of this progress report, we have completed an initial no-cost extension and will enter a second and final no-cost extension period to achieve all project goals by Q1 2024. What opportunities for training and professional development has the project provided?This project has provided training opportunities for post-doctoral fellows, graduate students, and undergraduate students. These junior scientists have been provided critical knowledge concerning rigorous study design, the management of regulatory documentation, and hands-on experience to become proficient in biochemical tools including LC-MS, HPLC, spectrophotometry, and qPCR; genomic analysis pipelines; and statistical analysis using R-software. Two students also gained proficiency in dietary analysis, with specific expertise to assess time-dependent changes in dietary polyphenols intakes during the randomized controlled trial by merging a USDA database (Flavonoid Content of Selected Foods) with NDSR dietary analysis software. Undergraduate students have also received hands-on mentoring from more senior graduate students and post-doctoral scholars concerning data management, database generation, and project management to enhance their interest to pursue advanced study in agricultural sciences. How have the results been disseminated to communities of interest?Project dissemination continues to be actively underway, through scientific publications and presentations that target the scientific community while also reaching the broader non-scientific community. We have published a full-length manuscript examining the impact of health status on green tea polyphenol bioavailability and metabolism. We have also presented findings to scientific audiences at national scientific conferences, university centers, and departments of nutrition and/or food science. We have also worked with media services to Issue a press release of preliminary findings demonstrating efficacy of green tea polyphenols to Improve gut health relative to glucose homeostasis. This press release was picked up by dozens of agencies globally. What do you plan to do during the next reporting period to accomplish the goals?This project is currently in a no-cost extension to accommodate the significant setbacks in progress that occurred due to the global pandemic. In this final project period, we expect to complete all project objectives and author at least 2 full-length research manuscripts to detail primary and secondary endpoints of the randomized controlled trial that was completed under this project. Because the randomized controlled trial was completed as proposed in the approved project (e.g., recruitment goals achieved), albeit with delays due to the pandemic, we expect that our experimental findings will significantly advance an understanding of the mechanisms and efficacy of green tea polyphenols to restore gut health in humans towards achieving systemic metabolic health.
Impacts
What was accomplished under these goals?
During the past reporting period, our focus has been placed on completing detailed biomolecular analyses and preparing manuscripts for consideration of peer-reviewed publication. We reported previously that the intervention phase of the randomized controlled placebo-controlled trial in healthy persons and persons with metabolic syndrome was completed. We have completed spectrophotometric measures of circulating glucose, endotoxin, liver function tests, expression profiles of pro-inflammatory genes from peripheral blood mononuclear cells, fecal short chain fatty acids, and circulating catechins. Rigorous assessment of dietary nutrient and polyphenol intakes have also been completed. In our first manuscript (in preparation for submission in Q2 2023), we will be reporting the primary outcome of the study (serum endotoxin) and its favorable relationship with green tea polyphenol-mediated improvements in gut barrier functions and lowering of circulating glucose in both health and metabolic syndrome persons. In addition to data demonstrating efficacy, we will also disseminate the safety of our intervention to have no adverse effects on biomarkers of liver function or other less concerning aspects (i.e., nausea, vomiting, and other minor adverse events). We will then direct our attention to data mining and detailed reporting of 16S metagenomic changes in gut microbial community structure and function in relation to the green tea polyphenol intervention. We have already identified that select bacteria populations have improved in response to green tea polyphenols, but have simultaneously noted significant inter-individual responses to treatment. We will therefore construct a statistical model to examine inter-relationships between/among circulating green tea catechins and their microbial metabolites, metrics of microbial diversity as well as bacterial enrichment/depletion, and short chain fatty acids relative to the observed improvements in gut barrier permeability in response to green tea polyphenols. Lastly, we completed and published a pharmacokinetic study in healthy persons and obese persons examining the bioavailability and metabolism of green tea polyphenols. Data show that obese persons have significantly lower bioavailability of all major catechins present in green tea (epigallocatechin gallate, epicatechin, epigallocatechin, epicatechin gallate) compared with healthy persons, consistent with a mechanism that impairs intestinal absorption. Further, we demonstrated that, regardless of health status, the bioavailability of microbial-derived catechin metabolites (valerolactones) were unaffected, but that these metabolites are absorbed to a much greater extent than catechins themselves. This provides premise for the potential health benefits of gut-derived catechin metabolites to mediate the health benefits of green tea independently and/or additively with catechins themselves.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
S Cao, EN Shaw, W Quarles, GY Sasaki, P Dey, JK Hodges, A Pokala, M Zeng, RS Bruno. (2022). Daily inclusion of resistant starch-containing potatoes in a Dietary Guidelines for Americans dietary pattern does not adversely affect cardiometabolic risk or intestinal permeability in adults with metabolic syndrome: A randomized controlled trial. Nutrients, 14(8):1545. doi: 10.3390/nu14081545
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
KR Weinhold, RR Andridge, JA Bomser, GY Sasaki, RS Bruno, TS Orchard. (2022). Sugars measured enzymatically in a fasting overnight urine sample are not sensitive biomarkers of dietary added sugar intake in postmenopausal women. Nutr Health, 2601060221106819. doi: 10.1177/02601060221106819.
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
X Sun, P Dey, RS Bruno, J Zhu. (2022). EGCG and catechin relative to green tea extract differentially modulate the gut microbial metabolome and liver metabolome to prevent obesity in mice fed a high-fat diet. J Nutr Biochem, 109:109094. doi: 10.1016/j.jnutbio.2022.109094.
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
L Chen, R Xu, J McDonald, RS Bruno, F Choueiry, J Zhu (2022). Dairy milk casein and whey proteins differentially alter the postprandial lipidome in persons with prediabetes: A comparative lipidomics study. J Agric Food Chem, 70(33):10209-10220. doi: 10.1021/acs.jafc.2c03662.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2022
Citation:
M Khalafi, JK Hodges, RS Bruno. (2022). A low-polyphenol diet during a randomized controlled crossover trial decreases polyphenol intakes without substantially affecting intakes of macronutrients and micronutrients in metabolic syndrome and healthy persons. OSU Denman Research Forum (Columbus, Ohio). Abstract/Poster.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2022
Citation:
M Khalafi, JK Hodges, RS Bruno. (2022). A low-polyphenol diet during a randomized controlled crossover trial decreases polyphenol intakes without substantially affecting intakes of macronutrients and micronutrients in metabolic syndrome and healthy persons. OSU Russel Klein Memorial Symposium (Columbus, Ohio). Abstract/Poster.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2022
Citation:
M Zeng, JK Hodges, GY Sasaki, S Cao,Y Vodovotz, RS Bruno. (2022). A green tea extract-rich confection in healthy and metabolic syndrome adults decreases small intestinal permeability in association with lower gut inflammation. Nutrition: International Meeting for the American Society for Nutrition. Abstract/Poster.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2022
Citation:
M Zeng, JK Hodges, GY Sasaki, S Cao,Y Vodovotz, RS Bruno. (2022). Daily ingestion of a catechin-rich green tea confection decreases intestinal permeability and inflammation in healthy and metabolic syndrome adults: a randomized, double-blind, placebo-controlled, crossover trial. OSU Russel Klein Memorial Symposium (Columbus, Ohio). Abstract/Poster.
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
H-Y Chen, A Almonte-Loya, F-Y Lay, M Hsu, E Johnson, E Gonzalez-Avalos, J Yin, RS Bruno, Q Ma, HE Ghoneim, DJ Wozniak, FE Harrison, C-WJ Lio. (2022). Epigenetic remodeling by vitamin C potentiates plasma cell differentiation. eLife, 11:e73754. doi: 10.7554/eLife.73754.
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
119. GY Sasaki, Y Vodovotz, Z Yu, RS Bruno. (2022). Catechin bioavailability following consumption of a green tea extract confection is reduced in obese persons without affecting gut microbial-derived valerolactones. Antioxidants, 11(12):2490. doi: 10.3390/antiox11122490.
- Type:
Book Chapters
Status:
Published
Year Published:
2022
Citation:
JK Hodges and RS Bruno (2022). Epigallocatechin-3-gallate: cardiometabolic benefits and metabolism. In: Tea as a Food Ingredient: Properties, Processing, and Health Aspects (1st ed.). Yin, J., Fu, Z., & Xu, Y. (Eds.). CRC Press. https://doi.org/10.1201/9781003152828
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2022
Citation:
JK Hodges, S Cao, M Zeng, A Pokala, S Rezaei, GY Sasaki, RS Bruno. (2022). Catechin-rich green tea extract reduced intestinal inflammation in metabolic syndrome and healthy adults. OSU Edward F. Hayes Graduate Research Forum (Columbus, Ohio). Abstract/Poster.
|
Progress 03/15/21 to 03/14/22
Outputs
Target Audience:The primary target audiences reached during this reporting period included phytochemical and functional food scientists and nutrition professionals. These persons received education concerning the health benefits of green tea polyphenols acting at the intestinal barrier relative to systemic inflammation. They were also provided information concerning the rigorous design of our completed randomized controlled trial that aims to demonstrate efficacy and research translation of green tea polyphenols to improve gut health. Interim findings were also shared with these audiences showing that daily supplementation of green tea catechins reduced gut barrier permeability in association with reducing intestinal inflammation. Changes/Problems:The major challenge experienced during this project was the restrictions imposed by the global pandemic that hindered research subject enrollment and ultimately a delay in completing the planned randomized controlled trial. During this pause in activity, we pursued a related objective to examine the differential bioavailability and metabolism of green tea catechins in relation to obesity status. A full-length manuscript is actively being prepared for publication in 2022 that communicates a mathematical compartmental modeling of catechins and the pools that are dysregulated by obesity status. With research activities now proceeding efficiently, we do not expect further challenges to address each of our study outcomes during the next reporting period. What opportunities for training and professional development has the project provided?Student and postdoctoral trainees have been provided professional development to learn how to rigorously implement a randomized controlled trial, manage regulatory paperwork (e.g., IRB, clinicaltrials.gov), and obtain training towards proficiency in bioanalytical techniques required to complete biospecimen analysis. These include LC/MS-based measures of short chain fatty acids, gut permeability probes, and circulating catechins. Spectrophotometry/ELISA-based training has been completed towards to the successful measure of clinical endpoints (e.g., glucose, liver function tests, lipids) and protein biomarkers of inflammation. Undergraduate students have also received mentoring from senior staff regarding data entry and analysis, and have utilized the data for local presentation. How have the results been disseminated to communities of interest?Project dissemination has been achieved, and remains underway, through scientific publications and presentations that target the scientific community but also reach the broader community of non-scientists. The research team has published the full methodology of the rationale, design, and procedures of this double-blind, randomized, placebo-controlled crossover trial (Hodges et al, 2019, Contemp Clin Trials Comm). We have also published a narrative review to describe the mechanisms by which catechins exhibit gut-level anti-inflammatory activities that alleviate systemic inflammation and metabolic dysfunction (Hodges et al, J Nutr Biochem, 2020). Dr. Bruno and junior personnel have also been active in providing local and national presentations to share interim findings of the research towards a long-term goal of preparing a series of publications to communicate the primary and secondary outcomes of the recently completed randomized controlled trial. What do you plan to do during the next reporting period to accomplish the goals?Due to the delays caused by the pandemic, the project was granted its first no-cost extension (through March 2023). We expect to use this period to complete all biospecimen analysis and prepare manuscripts for consideration of peer-reviewed publication. Specifically, a publication is planned to disseminate metrics of compliance, dietary analysis of nutrients and polyphenols, and measures of endotoxemia relative to gastrointestinal permeability and insulin resistance. We also plan a separate full-length manuscript to communicate the relationship between/among catechin-mediated changes in intestinal inflammation relative to systemic inflammation and the mediating effects of the gut microbiome. Ancillary studies are also planned to examine the fecal (microbial) metabolome relative to small intestinal and systemic inflammatory biomarkers.
Impacts
What was accomplished under these goals?
During the reporting period, we have nearly fully recovered from the challenges imposed by the global pandemic that deterred research progress in accordance with our planned timeline. Major accomplishments have included our successful completion of the intervention phase of a double-blind, placebo-controlled crossover trial in persons with metabolic syndrome and age- and gender-matched healthy persons who received a catechin-rich confection or matched placebo confection for 4-weeks. Biomolecular analyses of cryogenically preserved biospecimens are actively underway from the completed human trial. Interim findings indicate, regardless of health status, that all participants were compliant to instructions to follow a low-polyphenol diet, that compliance to test confections was greater than >90% (based on pill counts), and no adverse events occurred in relation to COVID-19 or any experimental procedures. We also provide novel evidence that the catechin-rich confection decreased small intestinal permeability regardless of health status, and these improvements occurred in association with favorable reductions in intestinal inflammation based on corroborating measures fecal calprotectin and myeloperoxidase. Measures of circulating catechins have been completed, and corroborate compliance to the appropriate test confection. All clinical measures have been completed, including glucose, liver function tests, and circulating lipids. Most show effects due to health status but without any effect of the green tea confection to normalize these clinical criteria. Metagenomic analysis is underway, with 16S rRNA sequencing complete and bioinformatic analysis in progress. During the next reporting period, we expect to complete all biospecimen analyses and prepare reports/manuscripts for consideration of peer-reviewed publication.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
H Chatelaine, P Dey, X Mo, RS Bruno, RE Kopec. (2020). Vitamin A and D absorption in adults with metabolic syndrome vs. healthy controls a pilot study utilizing targeted and untargeted LC-MS lipidomics. Mol Nutr Food Res, 2021;65(2):e2000413. doi: 10.1002/mnfr.202000413.
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
L Chen, S Zhang, X Sun, JD McDonald, RS Bruno, J Zhu. (2021). Application of comparative lipidomics to elucidate postprandial metabolic excursions following dairy milk ingestion in individuals with prediabetes. J Proteome Res, 2021; 20(5):2583-2595. doi: 10.1021/acs.jproteome.0c01009.
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
MT Goodus, KE Carson, AD Sauerbeck, P Dey, AN Alfredo, PG Popovich, RS Bruno, DM McTigue. (2021) Liver inflammation at the time of spinal cord injury enhances intraspinal pathology, liver injury, metabolic syndrome and locomotor deficits. Exp Neurol. 2021;342:113725. doi: 10.1016/j.expneurol.2021.113725
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
RS Bruno, A Pokala, M Torres-Gonzalez, CN Blesso. (2021). Cardiometabolic Health Benefits Of Dairy Milk Polar Lipids. Nutr Rev, 2021;79(Suppl 2):16-35. doi: 10.1093/nutrit/nuab085 .
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
X Sun, P Dey, RS Bruno, J Zhu. (202x). EGCG and catechin relative to green tea extract differentially modulate the gut microbial metabolome and liver metabolome to prevent obesity in mice fed a high-fat diet. J Nutr Biochem, In revision.
- Type:
Book Chapters
Status:
Published
Year Published:
2021
Citation:
JK Hodges and RS Bruno (2021). Epigallocatechin-3-gallate: cardiometabolic benefits and metabolism. In: Tea as Food Ingredient: Properties, Processing and Health Aspects (editor: John Shi), CRC Press, USA. In press.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2021
Citation:
RS Bruno. (2021). Advances in Bioactive Food Component Research. USDA W4002 Multistate Project Directors Meeting. Webinar hosted by University Illinois.
- Type:
Theses/Dissertations
Status:
Published
Year Published:
2020
Citation:
Sasaki GY. Dietary green tea to attenuate metabolic endotoxemia-associated inflammation along the gut-liver axis. The Ohio State University. Dissertation.
|
Progress 03/15/20 to 03/14/21
Outputs
Target Audience:In Year 2, target audiences reached included scientists in the phytochemical field and research participants. Phytochemical scientists were provided knowledge concerning our detailed research protocols to conduct a randomized controlled trial in persons with metabolic syndrome and healthy persons to test the hypothesis that green tea polyphenols will improve gut barrier function relative to systemic inflammation. These individuals also had opportunity to be apprised of preliminary results of the intervention trial and a separate study examining obesity on the pharmacokinetics and metabolism of green tea polyphenols. Research participants engaged in these studies have been educated on hypotheses concerning the putative anti-inflammatory benefits of green tea polyphenols on gut and metabolic health. Changes/Problems:The pause of in-person research activities involving human subjects (Mar-Aug 2020) hindered our ability to complete the intervention phase of the randomized controlled trial according to the plan approved in the application. This resulted in delays to collect biospecimens for bioanalytical measures and fecal samples that are required to inoculate the in vitro human colon model. With normal operations now fully resumed, we anticipate completing all project objectives as proposed albeit a no-cost extension will be requested in late-2021 to accommodate the significant delays attributed to the novel coronavirus pandemic. Because of the uncertainty surrounding research activities due to coronavirus-related pause in research activities, we did add a related objective to the underway project to maintain productivity associated with this application. Specifically, we are examining the bioavailability and metabolism of catechins in relation to health status (obese vs healthy persons) to better understand the anti-inflammatory activities of green tea catechins. As part of this work, we are also establishing a novel mathematical model to define how obesity status adversely affects catechin absorption, distribution, metabolism and elimination. These studies are expected to more fully inform future human intervention trials and/or help to identify the specific bioactive components of green tea. What opportunities for training and professional development has the project provided?These projects have provided training opportunities for undergraduate students, graduate students, as well as a postdoctoral scholar who coordinates the study. Undergraduate students have received training in human subject research protections and procedures necessary to perform human controlled trials with scientific rigor. The study coordinator and graduate students have become proficient in spectrophotometric techniques to quantify biomarkers of metabolic syndrome, HPLC analyses, and white blood cell RNA extraction. The post-doctoral scholar has also been trained to conduct LC-MS studies of gut barrier permeability and fecal short-chain fatty acids and will continue in training to achieve proficiency in metagenomic studies. How have the results been disseminated to communities of interest?The rationale, design, and methods of this double-blind, randomized, placebo-controlled crossover trial was described in a scientific paper, which was published during Year 1 (Hodges et al, 2019, Contemp Clin Trials Comm). In Year 2, the research team published a narrative review detailing the gut-level anti-inflammatory activities of green tea polyphenols that are likely responsible for alleviating systemic inflammation and metabolic dysfunction (Hodges et al, J Nutr Biochem, 2020); this manuscript directly supports the rationale for the present translational studies in persons with metabolic syndrome. Dr. Bruno (PD) also published a book chapter describing the anti-inflammatory activities of green tea catechins, with emphasis on outcomes from human observational and intervention studies. These collective works are anticipated to reach both the scientific community and broader community of non-scientists. What do you plan to do during the next reporting period to accomplish the goals?The next reporting period is dedicated to conducting biochemical and statistical analyses of all study endpoints. These include: analyzing the gut microbiota following metagenomic sequencing; conducting LC-MS studies to examine plasma catechins and metabolites and indices of gut permeability; quantifying pro-inflammatory proteins at the gut and pro-inflammatory genes in the systemic circulation; and assessing serum endotoxin and metabolic endpoints (glucose, insulin, liver function). Manuscript development is also expected to report the primary (serum endotoxin) and secondary (gut permeability) endpoints of the intervention study.
Impacts
What was accomplished under these goals?
The primary focus of this application is to conduct a cross-over, double-blind, placebo-controlled randomized controlled trial (RCT) to examine green tea catechins (4-wk) on gut barrier function and systemic inflammation in persons with metabolic syndrome (MetS) and healthy persons. At the time of Year 1 reporting (~March 2020), the global coronavirus pandemic prompted an uncertain but temporary pause of all in-person research activities at The Ohio State University. Recruitment of participants for the RCT was paused through August 2020 when it was deemed sufficiently safe to resume activities involving human research subjects. During that unexpected period, we published a narrative review article to detail the preclinical evidence by which green tea catechins alleviate gut barrier dysfunction and inflammation in support of the present translational studies. We also conducted rigorous biochemical analyses utilizing liquid chromatography-mass spectrometry (LC-MS) and archived urine and plasma samples from healthy persons versus obese persons who ingested green tea extract prior to time-dependent biospecimen collection over 24 hours. The initial intent of these studies was to examine the pharmacokinetics and bioavailability of green tea catechins and their microbial-derived metabolites. Findings supported the hypothesis that obese persons have reduced bioavailability of green tea catechins compared with healthy persons (P<0.05). In support of the objectives of the present application, plasma and urinary catechin data were utilized to establish a novel mathematical model to define obesity status on potential differences in catechin absorption, distribution, metabolism, and elimination. Preliminary evidence suggests differences by health status with respect to small intestinal absorption as well as extrahepatic trafficking of catechins. Immediately upon resuming research activities in August 2021, we enrolled the remaining participants for the RCT, which resulted in our successful completion of the 3-month intervention trial in Q1 2021 in accordance with our recruitment plan (n = 21 adults with metabolic syndrome and 19 age- and gender-matched healthy adults). Although expected attrition occurred (e.g. non-compliance), no adverse events occurred in relation to COVID-19 or any experimental procedures. Compliance based on counting of any returned green tea-rich confections was high (>90%), which will be verified objectively by biochemical analysis of catechins in plasma and urine samples. Efforts are currently directed at conducting biochemical analyses to perform metagenomic sequencing of the fecal microbiota, measures of inflammation-related biomarkers systemically and at the gut, and assessing pro-inflammatory gene expression in the systemic circulation. Participants' dietary records have been analyzed using NDSR dietary analysis software, and statistical analyses are forthcoming upon unblinding of the study code. Similarly, a panel of 9 fecal short-chain fatty acids (including straight chain and branched chain) was analyzed from all participants from both study phases using our in-house LC-MS technique that was established specifically for this application. During the next reporting period, we expect to complete studies under Aim 1-2, with studies under Aim 2 consisting of inoculating a human colon model with fecal samples (bacteria) from healthy participants and persons with metabolic syndrome to establish mechanistic information by which gut dysbiosis influences microbial metabolism of catechins. These studies will not only assess the effects of MetS but also whether these effects are localized to the proximal, transverse, or distal colon.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
MG Traber, GR Buettner, RS Bruno. (2019). The relationship between vitamin C status, the gut-liver axis, and metabolic syndrome. Redox Biology (Invited Review), 21:101091. doi: 10.1016/j.redox.2018.101091
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
P Dey, JB Kim, C Chitchumroonchokchai, J Li, GY Sasaki, BD Olmstead, KL Stock, JM Thomas-Ahner, SK Clinton, RS Bruno. (2019). Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis. Food Funct, 10, 6351-6361.
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
GY Sasaki, J Li, MJ Cichon, KM Riedl, RE Kopec, RS Bruno. (2019). Green tea extract treatment in obese mice with nonalcoholic steatohepatitis restores the hepatic metabolome in association with limiting endotoxemia-TLR4-NFkB-mediated inflammation. Mol Nutr Food Res, 63(24):e1900811. doi: 10.1002/mnfr.201900811.
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
P Dey, BD Olmstead, GY Sasaki, Y Vodovotz, Z Yu, RS Bruno (2020). Epigallocatechin gallate but not catechin prevents nonalcoholic steatohepatitis in mice similar to green tea extract while differentially affecting the gut microbiota. J Nutr Biochem, doi: 10.1016/j.jnutbio.2020.108455.
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
JK Hodges, GY Sasaki, RS Bruno. (2020). Anti-inflammatory activities of green tea catechins along the gut-liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies. J Nutr Biochem, 2020;85:108478. doi: 10.1016/j.jnutbio.2020.108478.
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
GY Sasaki, J Li, MJ Cichon, RE Kopec, RS Bruno. (2020). Catechin-rich green tea extract and the loss-of-TLR4 signaling differentially alter the hepatic metabolome in mice with nonalcoholic steatohepatitis. Submitted, Mol Nutr Food Res, 2020; doi: 10.1002/mnfr.202000998.R1.
- Type:
Journal Articles
Status:
Published
Year Published:
2021
Citation:
RS Bruno, AP Neilson, JD Lambert, N Moustaid-Moussa. (2020). Journal Of Nutritional Biochemistry Special Issue: Polyphenols, Obesity, And Cardiometabolic Health. J Nutr Biochem, 89:108565. doi: 10.1016/j.jnutbio.2020.108565.
- Type:
Book Chapters
Status:
Published
Year Published:
2019
Citation:
P Dey, GY Sasaki, RS Bruno. (2019). Green Tea: Composition, Metabolism, Bioavailability and Role in Preventing Chronic Diseases. In: Handbook of Nutraceuticals and Functional Foods, 3rd Edition (REC Wildman and RS Bruno, ed). In Press
- Type:
Books
Status:
Published
Year Published:
2019
Citation:
REC Wildman and RS Bruno. (2019). Handbook of Nutraceuticals and Functional Foods, 3rd Edition, Taylor and Francis (New York).
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Progress 03/15/19 to 03/14/20
Outputs
Target Audience:In Year 1, the target audience reached was primarily scientists interested in reviewing our published protocol detailing the dietary intervention involving a green tea catechin-rich confection that is actively underway. The secondary audience reached was research participants who were enrolled into the research to evaluate the effects of green tea catechins on parameters of gut health that influence inflammation and metabolic syndrome complications. Changes/Problems:While there are no methodological changes to our experimental approaches, the intervention phase of the randomized controlled trial has been temporarily suspend in accordance with institutional guidance issued in Mar 2020 in relation to the COVID-19 virus. We anticipate resumingnormal operations in Apr 2020. During this period, we will perform interim data analysis on food records and other non-biochemical endpoints and address federal regulatory aspects of the project. What opportunities for training and professional development has the project provided?These projects have provided training opportunities for undergraduate students, graduate students, as well as a postdoctoral scholar who coordinates the study. Undergraduate students have become trained in human subject research protections and procedures necessary to perform human controlled trials with scientific rigor. The study coordinator and graduate students have become proficient in spectrophotometric techniques that quantify biomarkers of metabolic syndrome, HPLC analyses, and white blood cell RNA extraction. How have the results been disseminated to communities of interest?The rationale, design, and methods of this double-blind, randomized, placebo-controlled crossover trial was described in a scientific paper, which was published during Year 1 (Hodges et al, 2019, Contemp Clin Trials Comm). What do you plan to do during the next reporting period to accomplish the goals?During the next reporting period, we plan to complete participant recruitment and the intervention in its entirety. Biospecimen analysis will begin immediately thereafter and reporting of the primary and select secondary endpoints is expected. Efforts will then be directed at research translation to support evidence-based dietary recommendations to alleviate endotoxemia-associated inflammatory responses that are implicated in cardiometabolic disorders (e.g. diabetes, fatty liver, cardiovascular disease, metabolic syndrome).
Impacts
What was accomplished under these goals?
Under Aim 1, we are actively recruiting participants through ads published in the university online newsletter, posters installed in the university buses, flyers posted in the buildings around campus, pamphlets placed in mailboxes of OSU employees and distributed by physicians in the nearby primary care clinics. Since August 2019, we received 445 e-mails and phone calls from potential participants. Of these, 224 were assessed for eligibility over the phone and 61 were invited for an in-person screening visit to assess blood levels of glucose and lipids. From those who were consented and screened for eligibility, 13 have completed all aspects of the 2-arm cross-over intervention and 7 have completed the first arm and await completion of wash-out to begin the second arm of the randomized controlled trial. (Note: as of March 13, 2020, institutional guidance was issued to temporarily pause all human intervention studies due to COVID-19 virus that is active globally). Adherence to intervention and low-polyphenol diet has been measured by monitoring food records completed by participants and by counting the confections retuned at each clinical visit. Based on these data, adherence is >93%. To date, there were no missed blood and urine sample collections and 61 out of 66 due fecal samples were collected, processed, aliquoted, and stored for later analysis. Participants also completed 67 out of 68 due food records (1 participant delivered a copy of their mid-intervention record in place of their post-intervention record and has not responded to e-mails asking for the correct version). To date, no adverse events were reported by participants to any of our intervention or sample collection procedures. On July 1, 2019, an amendment to the IRB protocol was approved containing an added measurement of trimethylamine N-oxide (TMAO), soluble cell surface receptor CD14, and lipopolysaccharide-binding protein (LBP) as complementary markers of metabolic endotoxemia, the primary outcome in this study. We have also increased the upper limit of blood pressure for eligible participants from 130/80 mmHg to 140/90 mmHg to match the eligibility requirements used in our other studies of metabolic syndrome and to ensure that we meet the recruitment goal. On July 9, 2019, we have measured the catechin profile of GTE extract purchased from Taiyo, Inc. for the purpose of this study. The extract contains 89% total catechins with the following distribution: 62% epigallocatechin gallate, 14% epigallocatechin, 10% epicatechin gallate, 13% epicatechin, and 2% catechin. This is a similar to what was observed in our previous studies and matches the freshly brewed green tea catechin profile. The catechin composition of GTE has been analyzed periodically and its composition remains stable (+/- 5% for each catechin). Under Aim 2, a pilot analysis by LC-MS/MS was performed of several fecal samples collected by participants to ensure that the catechin metabolites and short chain fatty acids are detectable.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Hodges JK, Zhu J, Yu Z, Vodovotz Y, Brock G, Sasaki GY, Dey P, Bruno RS. Intestinal-level anti-inflammatory bioactivities of catechin-rich green tea: rationale, design, and methods of a double-blind, randomized, placebo-controlled crossover trial in metabolic syndrome and healthy adults. Contemp Clin Trials Commun. 2019; 17:100495
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